Download PDF
Synlett 2002(2): 0280-0284
DOI: 10.1055/s-2002-19759
LETTER
© Georg Thieme Verlag Stuttgart · New York

Short and Versatile Two-Carbon Ring Expansion Reactions by Thermo-Isomerization: Novel Straightforward Synthesis of (±)-Muscone, Nor- and Homomuscones, and Further Macrocyclic Ketones

Matthias Nagel*a, Hans-Jürgen Hansena, Georg Fráterb
a Organisch-chemisches Institut der Universität, Winterthurerstr. 190, CH 8057- Zürich, Switzerland
Fax: +41(1)635 68 12; e-Mail: mnagel@access.unizh.ch;
b Givaudan Research Ltd, Überlandstr. 138, CH-8600 Dübendorf, Switzerland
Fax: +41(1)824 29 26; e-Mail: georg.frater@givaudan.com;
Further Information

Publication History

Received 3 September 2001
Publication Date:
02 February 2007 (online)

   Permissions and Reprints All articles of this category

Abstract

Thermo-isomerization of 1-vinyl substituted medium- and large-ring cycloalkanol derivatives in a flow reactor system at temperatures of 600 °C to about 650 °C leads directly to the ring-expanded macrocyclic ketones. Alkyl substituents at the vinylic moiety are transferred locospecifically to the ring-expanded ketone as corresponding α-, and β-substituents, respectively. This novel thermal 1,3-C shift reaction therefore provides a new access to short syntheses of many alkyl-substituted macrocyclic ketone derivatives [e.g. (±)-muscone and analogues] in a systematic manner.

Key words

ring expansions - macrocyclic ketones - dynamic gas phase thermo-isomerization - two- carbon ring insertion reactions - (±)-muscone syntheses

2

For a description of the thermo-izomerization procedure and the experimental setup, see ref. [1] and references therein.

3

All mentioned cycloalkanols were synthesized by addition of the corresponding commercially available vinylic halides (normally the bromide) to the ketone by using a Grignard reaction. The yields could be improved significantly by pre-complexation of the ketone with CeCl3, according to the analogous procedure described in ref. 1 for the simple 1-vinylcycloalkanols. The propynyl substituted alcohol derivatives 16 and 20 were obtained in a similar manner by addition of propynyl magnesium bromide to the parent ketone. The 1-cyclohexen-1-yl-cyclododecanol 28 was obtained via addition of the lithio cyclohexenyl intermediate according to ref. [27]

18

Selected characteristic data of enones 8: 1H NMR (300 MHz, CDCl3): (E)-8a: 6.84 [dq, J = 15.5, 7 Hz, H-C(2)], 6.12 [dq, J = 15.5, 1.7 Hz, H-C(3)], 1.87 (dd, J = 7, 1.5 Hz). (Z)-8a: 6.19 [m, 2 H, H-C(2,3)], 2.11 (d, J = 7 Hz). 13C NMR (75 MHz, CDCl3): 200.4 [s, C(4)], (E)-8a: 141.9 [d, C(2)], 131.9 [d, C(3)], 18.0 [q, C(1)]. (Z)-8a: 142.2 [d, C(2)], 127.6 [d, C(3)], 15.9 [q, C(1)].

24

Cyclododecanone (12, 60 g, 0.33 mol) was melted by keeping it at 65-70 °C, then t-BuOH (15 mL) and trimethyl sulfoxonium iodide (117 g, 0.52 mol, 1.6 mol equiv.) were added with stirring. The resulting pulpy suspension was kept at 70 °C and potassium t-butoxide (56 g, 0.5 mol) were added in several portions. After an induction period of several minutes the insoluble precipitates slowly dissolved, due to the formation of equimolar amounts of DMSO during the spiroepoxide formation. After stirring for 1.5 h, powdered KOH (2 g) was added to the mixture. The course of the reaction was then followed by GC (conversion up to 95%). When further addition of KOH resulted in no additional epoxide formation, the mixture was allowed to cool to r.t. and water (100 mL) was added slowly with stirring. The mixture was diluted with t-BuOMe and then washed several times with water and brine. The organic layer was dried on MgSO4 and the solvent removed. After bulb-to-bulb distillation, oxirane 15 was obtained as a colorless oil (61 g, containing 5-10% 12) and was used for the transformation into 14 without further purification.